1. Field of the Invention
The present invention relates to a peptide inhibiting a matrix metalloproteanases activity and use thereof.
2. Description of the Related Art
Matrix metalloproteinase (MMP) is a group of endopeptidase capable of degrading macro-biomolecule such as collagen, proteoglycan and gelatin. And MMP is classed as collagenase, gelatinase, stromelysin and Membrane-type MMP. All of MMP is expressed in form of proenzyme, and activated by cutting its portion out (Bond, J. S., et al., Int. J. Biochem., 75, 565-574 (1985); Chen, J. M., Chen, W. T., Cell, 48, 193-203 (1987); Harris, E. D. et al., Coll Rel Res, 4, 493-512 (1984)).
Collagenase acts on triple-helix form epileptic collagen, gelatin, and the like, and is known to three kinds of collagenase, such as fibroblast collagenase, neutrophilic leukocyte collagenase and collagenase-3. In addition, It has been reported that collagenase cuts off type I, II and III of collagen fibrils (Goldberg, G. I., et al, J. Biol. Chem., 261, 6600-6605 (1986); Fini, M. E., et al., Biochemistry, 26, 6155-6165 (1987)). Furthermore, it has been reported that these three collagenases have at least about 50% sequence identity (Borkakoti, et al., Nature Struct. Biol., 1, 106-110 (1994); EMBO, J., 13, 1263-1269 (1994)).
MMP falls into a propeptide domain, a catalytic domain and a c-terminal domain. MMP is made of cryptoplasmic form and secreted, and activated by cutting 80 amino acids of N-terminal propeptide domain out and removing cysteine residue of domain having PRCGVPD sequences (Van Wart, H. E. et al., Proc. Nati. Acad. Sci. USA, 87, 5578-5582 (1990)). It has been reported that activity of the activated MMP is inhibited by coupling with tissue inhibitor of matrix metalloproteinase (TIMP), the coupling is regulated by the catalytic domain (Murphy, et al., J. Niol. Chem., 267, 9612-9618 (1992)). Various forms of MMP have substrate specificity, and is expressed in metabolic process when need to degrade extracellular matrix or structure of collagen in normal tissues. MMP-associated disorder is atherosclerosis, inflammatory disease of the central nervous system, Alzheimer's disease, skin aging, rheumatoid arthritis, osteoarthritis, corneal ulcers, bone disease, albuminuria, abdominal aneurysm disease, degenerative cartilage loss due to traumatic joint injuries, demyelinating disease of central nervous system, cirrhosis, glomerular disease, Preterm premature rupture of membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy cardiomyopathy, immature retinopathy, keratoconus, Sjogren's syndrome, myopia, eye tumors, corneal transplant rejection, angiogenesis, cancer invasion and metastasis, and the like. As the disease progressed, the extracellular matrix of articular cartilage is destructed, though autoimmune disorder is cause of rheumatoid arthritis and osteoarthritis. Stromelysin is recognized as a major enzyme at these arthritis and joint trauma and plays an important role in conversion procollagenase into activated collagenase. Therefore, inhibition of MMP activity blocks progression of arthritis, and it has been reported that the MMP is derived from penetrating leukocyte, fibroblast or external microorganism.
Also, collagenase secreted by stimulation of inflammatory mediator and bacteria generate gingival retraction by degrading collagen which is substrate of periodontal tissue, and cause periodontal disease by progression of that. Activity of fibroblast collagenase and stromelysin separated from inflamed gum is shown, and it is revealed that a level of enzyme and observed gingivitis are correlated (Overall, C. M. et al., J. Periodontal Res. 22, 81-88(1987)).
MMP is related to pathogenesis of a central nerve system. It is assumed that MMP destroys myelin and blood-brain barrier by inflowing inflammatory mononuclear cell into central nerve, and it is involved in accumulation of amyloid beta protein in Alzheimer's disease (Yong, V W, et al., Trends Neurosci 21(2), 75-80 (1998)). Also, it has been reported that concentration of MMP is higher in Alzheimer's diseased brain than in normal brain (Leake A, Morris C M, & Whateley J. Neurosci Leu 291(3), 201-3(2000), and it has been reported that level of gelatinase in cerebrospinal fluid is related to multiple sclerosis and other nerve disease and contributes accumulation of amyloid beta protein after degrading it (Backstrom J R, et al., J neurosci 16(24), 7910-9 (1996)).
In addition, because MMP induces skin aging, inhibition of MMP anticipates treatment and prevention of wrinkle; furthermore MMP facilitates angiogenesis and cancer invasion and metastasis through basilar membrane degradation. Therefore, there is a need for the development of drugs which is capable of inhibiting MMP because MMP not only plays an important role in cancer invasion and metastasis through basilar membrane degradation but also mediates various diseases. However, there is a need for the development of nontoxic agents as MMP activity inhibitor because the inhibitor can use in ideal medicine only if it can be safely with long-term use.
Furthermore, study on MMP inhibitors has been actively conducted for effective treatment of various MMP-mediated diseases, and the development of MMP inhibitors is used in treatment of various diseases effectively.
Throughout this application, various patents and publications are referenced, and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.